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Abstract Background Antenatal corticosteroids are recommended for women at risk of preterm birth from 24 to 34 weeks’ gestation as they reduce neonatal morbidity and mortality, but evidence regarding their long-term effects on offspring is limited. This study assessed general health and social outcomes 50 years after antenatal exposure to corticosteroids. Methods We assessed 424 adult offspring of women who participated in the first randomised, double-blind, placebo-controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome. The first 717 mothers received two intramuscular injections of betamethasone (6 mg betamethasone sodium phosphate and 6 mg betamethasone acetate) or placebo given 24 h apart and the subsequent 398 received two injections of double dose betamethasone (12 mg betamethasone sodium phosphate and 12 mg betamethasone acetate) or equivalent volume of placebo. Follow-up included a health questionnaire and consent for access to administrative data sources. Outcome categories included mental health (depression, anxiety, bipolar affective disorder, schizophrenia and treatment or hospital admission for any mental health disorder), general health (chronic kidney disease, cancer diagnosis, bone fracture, oral health, allergies, functional difficulties and physical activity) and social outcomes (educational attainment, employment and criminal convictions). Investigators remained blinded to treatment allocation. Analyses were adjusted for gestational age at entry, sex and clustering. Results We assessed 424 adult offspring (46% of survivors; mean [SD] age 49.3 [1.0] years; 212 [50%] female). There was no difference in mental health, general health and social outcomes between those exposed to betamethasone and those exposed to placebo, with the exception that osteoporotic site fracture in adulthood was more likely to have occurred in the betamethasone group compared with placebo (adjusted relative risk 1.57, 95% CI 1.00, 2.48, p = 0.05). No dose–effect relationship was evident and there was no difference in the proportion with at least one fracture. Follow-up rate and lack of in-person assessments were the main limitations. Conclusions There is no evidence that antenatal corticosteroids have clinically important effects on general health and social outcomes up to 50 years of age.

Abstract A transtibial prosthetic interface typically comprises a compliant liner and an outer rigid socket. The preponderance of today’s conventional liners are mass produced in standard sizes, and conventional socket design is labor-intensive and artisanal, lacking clear scientific rationale. This work tests the clinical efficacy of a novel, physics-based digital design framework to create custom prosthetic liner-socket interfaces. In this investigation, we hypothesize that the novel digital approach will improve comfort outcomes compared to a conventional method of liner-socket design. The digital design framework generates custom transtibial prosthetic interfaces starting from MRI or CT image scans of the residual limb. The interface design employs FEA to simulate limb deformation under load. Interfaces are fabricated for 9 limbs from 8 amputees (1 bilateral). Testing compares novel and conventional interfaces across four assessments: 5-min walking trial, thermal imaging, 90-s standing pressure trial, and an evaluation questionnaire. Outcome measures include antalgic gait criterion, skin surface pressures, skin temperature changes, and direct questionnaire feedback. Antalgic gait is compared via a repeated measures linear mixed model while the other assessments are compared via a non-parametric Wilcoxon sign-rank test. A statistically significant ( $$P=0.032$$ ) decrease in pain is demonstrated when walking on the novel interfaces compared to the conventional. Standing pressure data show a significant decrease in pressure on novel interfaces at the anterior distal tibia ( $$P = 0.012$$ ), with no significant difference at other measured locations. Thermal results show no statistically significant difference related to skin temperature. Questionnaire feedback shows improved comfort on novel interfaces on posterior and medial sides while standing and the medial side while walking. Study results support the hypothesis that the novel digital approach improves comfort outcomes compared to the evaluated conventional method. The digital interface design methodology also has the potential to provide benefits in design time, repeatability, and cost.

The implementation of screening colonoscopy with polyp removal has significantly decreased mortality rates associated with colorectal cancer (CRC), although it remains a major cause of cancer-related deaths globally. CRC typically originates from adenomatous polyps, and increased removal of these growths has led to reduced CRC incidence and mortality. Endoscopic polypectomy techniques, including hot and cold snare polypectomy, play a pivotal role in this process. While both methods are effective for small polyps (10 mm), particularly those with advanced features, pose increased cancer risks and often require meticulous assessment and advanced endoscopic techniques, including endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), for resection.This chapter also provides a practical overview of endoscopic techniques for managing colonic obstructions and pericolonic fluid collections, detailing their indications, advantages, disadvantages, and complications. The goal is to improve understanding and application in clinical practice. Additionally, we provide a summary of endoscopic closure techniques that have revolutionized the management of perforations and fistulas, offering safe and effective alternatives to surgery.

Abstract Spontaneous symmetry breaking and emergent polar order are each of fundamental importance to a range of scientific disciplines, as well as generating rich phase behaviour in liquid crystals (LCs). Here, we show the union of these phenomena to lead to two previously undiscovered polar liquid states of matter. Both phases have a lamellar structure with an inherent polar ordering of their constituent molecules. The first of these phases is characterised by polar order and a local tilted structure; the tilt direction processes about a helix orthogonal to the layer normal, the period of which is such that we observe selective reflection of light. The second new phase type is anti-ferroelectric, with the constituent molecules aligning orthogonally to the layer normal. This has led us to term the phases the $${{{{{\rm{Sm}}}}}}{{{{{{\rm{C}}}}}}}_{{{{{{\rm{P}}}}}}}^{{{{{{\rm{H}}}}}}}$$ Sm C P H and SmAAF phases, respectively. Further to this, we obtain room temperature ferroelectric nematic (NF) and $${{{{{\rm{Sm}}}}}}{{{{{{\rm{C}}}}}}}_{{{{{{\rm{P}}}}}}}^{{{{{{\rm{H}}}}}}}$$ Sm C P H phases via binary mixture formulation of the novel materials described here with a standard NF compound (DIO), with the resultant materials having melting points (and/or glass transitions) which are significantly below ambient temperature. The new soft matter phase types discovered herein can be considered as electrical analogues of topological structures of magnetic spins in hard matter.

Abstract Rangelands, covering half of the global land area, are critically degraded by unsustainable use and climate change. Despite their extensive presence, global assessments of rangeland condition and sustainability are limited. Here we introduce a novel analytical approach that combines satellite big data and statistical modeling to quantify the likelihood of changes in rangeland conditions. These probabilities are then used to assess the effectiveness of management interventions targeting rangeland sustainability. This approach holds global potential, as demonstrated in Mongolia, where the shift to a capitalist economy has led to increased livestock numbers and grazing intensity. From 1986 to 2020, heavy grazing caused a marked decline in Mongolia’s rangeland condition. Our evaluation of diverse management strategies, corroborated by local ground observations, further substantiates our approach. Leveraging globally available yet locally detailed satellite data, our proposed condition tracking approach provides a rapid, cost-effective tool for sustainable rangeland management.

Objectives: To investigate the associations of n-3 fatty acid intake with handgrip strength and muscle mass indices in older adults. A secondary aim was to investigate whether these associations differed by physical activity status. Research methods & procedures: A cross-sectional study included 53,170 participants aged 60 years and over from the UK biobank (25,324 men and 27,846 women). The primary outcomes were grip strength index and muscle mass index, the predictor variable was n-3 fatty acid intake and the covariates were age, ethnicity, Townsend deprivation index, physical activity, multimorbidity count, total energy intake, body fat percentage and the month of assessment. Multivariable linear regression analyses were performed across 5 models. Model 1 was unadjusted; model 2 adjusted for age, ethnicity, deprivation index and month of assessment; model 3 adjusted as in model 2 plus total energy intake; model 4 as in model 2 plus multimorbidity count; and model 5 as in model 4 plus body fat percentage. Results: In model 5, higher n-3 fatty acid intake was positively associated with the grip strength index in women. For each additional gram of n-3 fatty acid consumed per day, there was an increase of 0.03 kg/m2 (95% CI: 0.00 to 0.06 kg/m2) in active women and 0.04 kg/m2 (95% CI: 0.00 to 0.07 kg/m2) in inactive women. However, no significant associations were observed in men, whether active (p = 0.405) or inactive (p = 0.323). Additionally, no significant associations were found between n-3 fatty acid intake and muscle mass index in either active (p = 0.858) or inactive (p = 0.250) men, or in active (p = 0.909) or inactive (p = 0.187) women. Conclusion: Although n-3 fatty acid intake was associated with grip strength index in older women, regardless of their activity status, the magnitude of this association was very small and unlikely to be clinically relevant. Additionally, n-3 fatty acid was not associated with muscle mass index.

Introduction The well-being of healthcare workers (HCWs) is critical to providing excellent care. Recent evidence concerns the well-being of emergency department (ED) HCWs in New Zealand, with high levels of burnout found in a 2020 survey. This threat to providing high-quality acute care warrants improvement interventions. The causes of burnout are complex and multifactorial, the solutions are not straightforward.Methods and analysis A prospective, multisite, before and after, mixed methods study assessing a multicomponent intervention, adaptable to local context, that targets three organisation levels (the individual, the group and the system levels) and meaningfully involves frontline HCWs may reduce HCW burnout and improve HCW well-being. Individual HCWs will choose from three individual-level psychological interventions and participate in those most appropriate for them. Local champions will decide which group-level intervention their ED will use. The system-level intervention will build capacity and capability for quality improvement (QI) with QI training and the establishment of a Quality Improvement Learning System. This system-level intervention has several important features that may ultimately empower HCWs to contribute to improving the quality of ED healthcare.We will enrol nine EDs, from which there will be at least 900 HCW participants. EDs will be enrolled in three waves from March 2023 to April 2024, with interventions taking place in each ED over 12 months.Methods of assessment will include baseline and repeat survey measures of burnout and well-being. Process evaluation at each ED will provide details of context, the intervention and the fidelity of the implementation.Ethics and dissemination Ethics committee approval was provided, with locality approval at each site.Individual site feedback will be provided to each ED and executive leadership. Dissemination of findings will be through publication in peer-reviewed journals, presentation at national and international scientific meetings and through national healthcare quality bodies.Trial registration number Australia New Zealand Clinical Trials Registry (ACTRN12623000342617).

Not available.

Abstract Feeding ecology is an essential component of an organism's life, but foraging comes with risks and energetic costs. Species in which populations exhibit more than one feeding strategy, such as sea turtles, are good systems for investigating how feeding ecology impacts life‐history traits, reproduction and carried over effects across generations. Here, we investigated how the feeding ecology of loggerhead sea turtles (Caretta caretta) nesting at the Cabo Verde archipelago correlates with reproductive outputs and offspring quality. We determined the feeding ecology of female turtles before and during the breeding season from stable isotope analysis of carbon and nitrogen and correlated isotopic ratio with female and offspring traits. We found that female turtles feeding at higher trophic positions produced larger clutches. We also found that females with higher δ13C values, typical of productive foraging areas, had greater fat reserves, were less likely to be infected by leech parasites and produced heavier offspring. The offspring of infected mothers with higher δ13C values performed best in crawling and self‐righting trials than those of non‐infected mothers with higher δ13C values. This study shows adult female loggerheads that exploit productive areas build capital reserves that impact their reproductive success and multiple proxies for offspring quality. Overall, our findings provide valuable insights into the complex interplay between feeding ecology and reproductive success, and reveal the transgenerational carry‐over effects of both feeding ecology and health on offspring quality in sea turtles.

ABSTRACT Purpose: Smoking is a recognized risk factor for bladder BC and lung cancer LC. We investigated the enduring risk of BC after smoking cessation using U.S. national survey data. Our analysis focused on comparing characteristics of LC and BC patients, emphasizing smoking status and the latency period from smoking cessation to cancer diagnosis in former smokers. Materials and Methods: We analyzed data from the National Health and Examination Survey (2003-2016), identifying adults with LC or BC history. Smoking status (never, active, former) and the interval between quitting smoking and cancer diagnosis for former smokers were assessed. We reported descriptive statistics using frequencies and percentages for categorical variables and median with interquartile ranges (IQR) for continuous variables. Results: Among LC patients, 8.9% never smoked, 18.9% active smokers, and 72.2% former smokers. Former smokers had a median interval of 8 years (IQR 2-12) between quitting and LC diagnosis, with 88.3% quitting within 0-19 years before diagnosis. For BC patients, 26.8% never smoked, 22.4% were active smokers, and 50.8% former smokers. Former smokers had a median interval of 21 years (IQR 14-33) between quitting and BC diagnosis, with 49.3% quitting within 0-19 years before diagnosis. Conclusions: BC patients exhibit a prolonged latency period between smoking cessation and cancer diagnosis compared to LC patients. Despite smoking status evaluation in microhematuria, current risk stratification models for urothelial cancer do not incorporate it. Our findings emphasize the significance of long-term post-smoking cessation surveillance and advocate for integrating smoking history into future risk stratification guidelines.

Abstract Most ecological studies attempting to understand causes of population dynamics and community structure disregard intraspecific trait variation. We quantified the importance of natural intra‐cohort variation in body size and density of juveniles for recruitment of a sessile marine organism, the barnacle Semibalanus balanoides. Barnacles are representative of species organised in metapopulations, that is, as open local populations connected by larval dispersal. We tracked the individual growth and survival of a cohort of juvenile barnacles from two shores of North Wales. Barnacles settled as larvae in spring of 2002 on previously cleared rock. The density of these new recruits was experimentally manipulated in June and randomly selected individuals were monitored from June to October to evaluate the role of barnacle size and density in predicting survival. In doing so we characterised density at three spatial scales (quadrat: 25 cm2, cells within quadrats: 25 mm2 and neighbourhood: number of neighbours in physical contact with the target barnacle). At all scales, variations in juvenile body size exacerbated the effect of density‐dependent mortality on population size. While density‐dependent mortality was very intense in the small‐sized individuals, large‐sized individuals experienced very weak density‐dependent mortality and showed high survival rates. Using the concept of ‘Jensen inequality’, we show that important biases in estimations of survival, based on population size only, occur at high barnacle densities, where survival is low. Our study highlights the role of body size variation in understanding dynamics of open populations.

Cirrodrilus makinoi (Yamaguchi, 1934) has not been identified since it was originally described from the Japanese crayfish, Cambaroides japonicus (De Haan, 1841) on Hokkaido Island, northern Japan. A critical morphological comparison of the original and new material of C. makinoi with those of closely related C. tsugarensis Gelder and Ohtaka, 2000, from Honshu Island, reveals there are no differentiating morphological character to separate the two species. A molecular study using the mitochondrial cytochrome c oxidase subunit I gene supports this view, therefore, C. tsugarensis becomes a subjective junior synonym of C. makinoi. Another species resembling C. makinoi, C. homodontus Yamaguchi, 1932 is confirmed to be a distinct species and both are redescribed based on the original and new material.

Abstract Coastal communities and their landscapes are subject to constant change, and today face new challenges as a result of climate change and the sustainable energy transition. To ensure the resilience of coastal communities to ongoing changes in the natural and constructed environment, it is imperative that planners and other decision‐makers understand the importance of local places to residents. We used an interdisciplinary, mixed‐methods approach to study relationships between coastal residents and places in south Co. Wicklow, Ireland, introducing the concept of ‘affective engagement’. Grounded in new materialist theory (notably actor–network theory), this term connects the meaning derived by residents from their relationships with coastal places (‘affect’) to the extent of their material interactions (‘engagement’). ‘Affect’ was determined from thematic analysis of interviews and open questionnaire responses, as well as place attachment scales included in the questionnaire. Measures describing the strength of the relationship between residents and coastal places were used as a proxy for ‘engagement’. To understand how experienced meaning and material interaction interlink, principal component analysis (PCA) was used to join and visually explore the different measures of ‘affect’ and ‘engagement’. Potentially mediating sociodemographic variables were investigated using a permutational multivariate analysis of variance (PERMANOVA). The majority of self‐selected study participants displayed strong place attachment to their most frequently visited places. We found that affective engagement does not vary with age, gender or type of place. Participants favoured natural and constructed places in equal measure. This implies that constructed places can be of high value due to their different functions for different individuals, and that landscape transformations may impact on coastal residents if they cause a change in functionality. We found two domains comprising affective engagement that are not measurable by quantitative or qualitative data alone. The first of these domains is driven by attachments to places, and the other by meanings relating to either personal or social fulfilment afforded by a place. Our findings may help planners better understand the meanings behind local support for (or resistance against) landscape transformations, and how residents' affective engagement might be impacted by proposed interventions. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Importance Quantitative electroencephalography (qEEG) has been used in the neonatal intensive care unit (NICU) for several decades. Recent innovations have led to renewed interest in expanding its role in the NICU with the goal of improving both acute care of neonates in the NICU and longer‐term outcomes. Observations EEG in the NICU is primarily used to identify neonatal seizures. Sophisticated analysis of EEG can detect other acute neurological emergencies and provide additional information about short‐ and long‐term neurodevelopmental and epileptic prognosis. Using EEG for these additional findings may be limited by access to EEG resources and a constrained supply of neonatal neurophysiologists who can consistently evaluate unique neonatal EEG patterns. Relevance Quantitative EEG analysis is a rapidly developing technology with the potential to augment and support the interpretation of neonatal EEGs. This review focuses on the status of qEEG use in the NICU for identification and prediction of seizures and use in neuroprognostication. It also examines areas of promise for bedside qEEG applications.

BackgroundAntenatal corticosteroids for women at risk of preterm birth reduce neonatal morbidity and mortality, but there is limited evidence regarding their effects on long-term health. This study assessed cardiovascular outcomes at 50 years after antenatal exposure to corticosteroids.Methods and findingsWe assessed the adult offspring of women who participated in the first randomised, double-blind, placebo-controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (RDS) (1969 to 1974). The first 717 mothers received 2 intramuscular injections of 12 mg betamethasone or placebo 24 h apart and the subsequent 398 received 2 injections of 24 mg betamethasone or equivalent volume of placebo. Follow-up included a health questionnaire and consent to access administrative data sources. The co-primary outcomes were the prevalence of cardiovascular risk factors (any of hypertension, hyperlipidaemia, diabetes mellitus, gestational diabetes mellitus, or prediabetes) and age at first major adverse cardiovascular event (MACE) (cardiovascular death, myocardial infarction, coronary revascularisation, stroke, admission for peripheral vascular disease, and admission for heart failure). Analyses were adjusted for gestational age at entry, sex, and clustering. Of 1,218 infants born to 1,115 mothers, we followed up 424 (46% of survivors; 212 [50%] female) at mean (standard deviation) age 49.3 (1.0) years. There were no differences between those exposed to betamethasone or placebo for cardiovascular risk factors (159/229 [69.4%] versus 131/195 [67.2%]; adjusted relative risk 1.02, 95% confidence interval [CI] [0.89, 1.18;]; p = 0.735) or age at first MACE (adjusted hazard ratio 0.58, 95% CI [0.23, 1.49]; p = 0.261). There were also no differences in the components of these composite outcomes or in any of the other secondary outcomes. Key limitations were follow-up rate and lack of in-person assessments.ConclusionsThere is no evidence that antenatal corticosteroids increase the prevalence of cardiovascular risk factors or incidence of cardiovascular events up to 50 years of age. Established benefits of antenatal corticosteroids are not outweighed by an increase in adult cardiovascular disease.

Nanomaterial solutions to sustainable development goals are hindered in their path to commercialisation by an early-stage reliance on single metric optimisation. Here we formulate the PSEC challenge (Performance, Scalability, Environment and Cost) to integrate broader sustainability thinking with precise technical solutions and so enable successful commercialisation of these advanced materials.

Abstract Background We previously demonstrated that a heuristic (i.e., evidence-based, rounded yet practical) cadence threshold of ≥ 100 steps/min was associated with absolutely-defined moderate intensity physical activity (i.e., ≥ 3 metabolic equivalents [METs]) in older adults 61–85 years of age. Although it was difficult to ascertain achievement of absolutely-defined vigorous (6 METs) intensity, ≥ 130 steps/min was identified as a defensible threshold for this population. However, little evidence exists regarding cadence thresholds and relatively-defined moderate intensity indicators, including ≥ 64% heart rate [HR] maximum [HRmax = 220-age], ≥ 40% HR reserve [HRR = HRmax-HRresting], and ≥ 12 Borg Scale Rating of Perceived Exertion [RPE]; or vigorous intensity indicators including ≥ 77%HRmax, ≥ 60%HRR, and ≥ 14 RPE. Purpose To analyze the relationship between cadence and relatively-defined physical activity intensity and identify relatively-defined moderate and vigorous heuristic cadence thresholds for older adults 61–85 years of age. Methods Ninety-seven ostensibly healthy adults (72.7 ± 6.9 years; 49.5% women) completed up to nine 5-min treadmill walking bouts beginning at 0.5 mph (0.8 km/h) and progressing by 0.5 mph speed increments (with 2-min rest between bouts). Directly-observed (and video-recorded) steps were hand-counted, HR was measured using a chest-strapped monitor, and in the final minute of each bout, participants self-reported RPE. Segmented mixed model regression and Receiver Operating Characteristic (ROC) curve analyses identified optimal cadence thresholds associated with relatively-defined moderate (≥ 64%HRmax, ≥ 40%HRR, and ≥ 12 RPE) and vigorous (≥ 77%HRmax, ≥ 60%HRR, and ≥ 14 RPE) intensities. A compromise between the two analytical methods, including Youden’s Index (a sum of sensitivity and specificity), positive and negative predictive values, and overall accuracy, yielded final heuristic cadences. Results Across all relatively-defined moderate intensity indicators, segmented regression models and ROC curve analyses identified optimal cadence thresholds ranging from 105.9 to 112.8 steps/min and 102.0-104.3 steps/min, respectively. Comparable values for vigorous intensity indicators ranged between126.1-132.1 steps/min and 106.7–116.0 steps/min, respectively. Regardless of the relatively-defined intensity indicator, the overall best heuristic cadence threshold aligned with moderate intensity was ≥ 105 steps/min. Vigorous intensity varied between ≥ 115 (greater sensitivity) or ≥ 120 (greater specificity) steps/min. Conclusions Heuristic cadence thresholds align with relatively-defined intensity indicators and can be useful for studying and prescribing older adults’ physiological response to, and/or perceived experience of, ambulatory physical activity. Trial registration Clinicaltrials.gov NCT02650258. Registered 24 December 2015.

Ownership of cattle in Indonesia is dominated by smallholder farmers, who rely heavily on low-quality mature grasses and crop residues as animal feed. Forage tree legumes (FTLs) provide a practical and profitable option for supplying nutrients limiting cattle growth and reproduction, especially during the dry months. Indigofera zollingeriana is a tall, high-yielding plant under investigation as feed, which can produce edible plant material exceeding 4 t dry matter (DM)/ha/harvest, when cut every 68 days. I. zollingeriana is adapted to a relatively wide range of climatic conditions and soil-types, with notable high tolerance of acidic soils. Forage quality is high, with high crude protein (265 g/kg DM average) and low fiber (367 g neutral detergent fiber/kg DM) concentrations and high in vitro DM digestibility (72.6%). It contains no identified anti-nutritional compounds but concentration of indospicine, a recognized toxic contaminant in some species of Indigofera, is currently unknown. Information on animal responses to feeding I. zollingeriana is limited, especially for cattle, but research suggests growth responses in goats are comparable with those for other available FTLs. Research to date suggests I. zollingeriana could be a valuable addition to FTLs currently available in Indonesia, especially for acidic soils, but further information is required on performance on saline soils, persistence under regular harvesting, indospicine status, acceptance by cattle and effects on their productivity.

Abstract E3 ubiquitin ligases are critical to the protein degradation pathway by catalyzing the final step in protein ubiquitination by mediating ubiquitin transfer from E2 enzymes to target proteins. Nedd4 is a HECT domain-containing E3 ubiquitin ligase with a wide range of protein targets, the dysregulation of which has been implicated in myriad pathologies, including cancer and Parkinson's disease. Towards the discovery of compounds disrupting the auto-ubiquitination activity of Nedd4, we developed and optimized a TR-FRET assay for high-throughput screening. Through selective screening of a library of potentially covalent compounds, compounds 25 and 81 demonstrated apparent IC50 values of 52 µM and 31 µM, respectively. Tandem mass spectrometry (MS/MS) analysis confirmed that 25 and 81 were covalently bound to Nedd4 cysteine residues (Cys182 and Cys867). In addition, 81 also adducted to Cys627. Auto-ubiquitination assays of Nedd4 mutants featuring alanine substitutions for each of these cysteines suggested that the mode of inhibition of these compounds occurs through blocking the catalytic Cys867. The discovery of these inhibitors could enable the development of therapeutics for various diseases caused by Nedd4 E3 ligase dysregulation.

Neuromuscular junction (NMJ) dysfunction underlies several diseases, including congenital myasthenic syndromes (CMSs) and motor neuron disease (MND). Molecular pathways governing NMJ stability are therefore of interest from both biological and therapeutic perspectives. Muscle-specific kinase (MuSK) is necessary for the formation and maintenance of post-synaptic elements of the NMJ, and downstream of tyrosine kinases 7 (DOK7) is crucial for activation of the MuSK pathway. Overexpression of DOK7 using AAV9 has been shown to ameliorate neuromuscular pathology in pre-clinical disease models of CMS and MND. However, long-term consequences of DOK7 expression have been sparsely investigated and targeted overexpression of DOK7 in skeletal muscle yet to be established. Here, we developed and characterized a novel AAV9-DOK7 facilitating forced expression of DOK7 under a skeletal muscle-specific promoter. AAV9-tMCK-DOK7 was systemically delivered to newborn mice that were monitored over 6 months. DOK7 overexpression was restricted to skeletal muscles. Body weight, blood biochemistry, and histopathological assessments were unaffected by AAV9-tMCK-DOK7 treatment. In contrast, forced expression of DOK7 resulted in enlargement of both the pre- and post-synaptic components of the NMJ, without causing denervation. We conclude that muscle-specific DOK7 overexpression can be achieved in a safe manner, with the capacity to target NMJs in vivo.

Summary: Coral reefs underpin the environmental, social, and economic fabrics of much of the world's tropical coast. Yet, the fine-scale distribution and composition of coral reefs have never been reported consistently across the planet. Here, we present new area estimates enabled by global geomorphic zone and benthic substrate maps at 5 m pixel resolution. We revise global coral reef estimates to 348,361 km2 of shallow coral reefs and 80,213 km2 (46,237–106,319 km2, 95% confidence interval) of coral habitat. The mapping used more than 1.5 million training samples supported by 480+ data contributions to deploy a coral reef classification of over 100 trillion pixels from the Sentinel-2 satellites and the Planet Dove CubeSat constellation. The publicly available maps are accessible via the Allen Coral Atlas and Google Earth Engine and are already being used by thousands of people to improve the conservation, management, and research of coral reef ecosystems. Science for society: Coral reefs possess a quarter of all marine life and contribute to the well-being and livelihoods of a billion people worldwide. Maps of ecosystems underpin many science and conservation activities, but until recently, there were no consistent high-resolution maps of the world’s coral reefs. In this paper, we describe new global coral reef maps from the Allen Coral Atlas, detailing the underlying methodology and our new understanding of the global distribution of coral reefs. The transparent and repeatable nature of our mapping framework allows the maps to be updated based on user feedback, and the ease of access has led to downstream applications such as coral bleaching monitoring and usage in scientific, management, and conservation activities. Hundreds of thousands of people have already accessed the maps, and they are already being used directly around the world for marine spatial planning, marine protected areas, environmental accounting and assessments, restoration, and education.

Abstract All animals and plants respond to changes in the environment during their life cycle. This flexibility is known as phenotypic plasticity and allows organisms to cope with variable environments. A common source of environmental variation is predation risk, which describes the likelihood of being attacked and killed by a predator. Some species can respond to the level of predation risk by producing morphological defences against predation. A classic example is the production of so‐called ‘neckteeth’ in the water flea, Daphnia pulex, which defend against predation from Chaoborus midge larvae. Previous studies of this defence have focussed on changes in pedestal size and the number of spikes along a gradient of predation risk. Although these studies have provided a model for continuous phenotypic plasticity, they do not capture the whole‐organism shape response to predation risk. In contrast, studies in fish and amphibians focus on shape as a complex, multi‐faceted trait made up of different variables. In this study, we analyse how multiple aspects of shape change in D. pulex along a gradient of predation risk from Chaoborus flavicans. These changes are dominated by the neckteeth defence, but there are also changes in the size and shape of the head and the body. We detected change in specific modules of the body plan and a level of integration among modules. These results are indicative of a complex, multi‐faceted response to predation and provide insight into how predation risk drives variation in shape and size at the level of the whole organism.

Abstract Human activities have facilitated the invasion of freshwater ecosystems by various organisms. Especially, invasive bivalves such as the quagga mussels, Dreissena bugensis, have the potential to alter ecosystem function as they heavily affect the food web. Quagga mussels occur in high abundance, have a high filtration rate, quickly spread within and between waterbodies via pelagic larvae, and colonize various substrates. They have invaded various waterbodies across the Northern Hemisphere. In Central Europe, they have invaded multiple large and deep perialpine lakes with first recordings in Lake Geneva in 2015 and 2016 in Lake Constance. In the deep perialpine lakes, quagga mussels quickly colonized the littoral zone but are also abundant deeper (>80 m), where they are often thinner and brighter shelled. We analysed 675 quagga mussels using ddRAD sequencing to gain in‐depth insights into the genetic population structure of quagga mussels across Central European lakes and across various sites and depth habitats in Lake Constance. We revealed substantial genetic differentiation amongst quagga mussel populations from three unconnected lakes, and all populations showed high genetic diversity and effective population size. In Lake Constance, we detected no genetic differentiation amongst quagga mussels sampled across different sites and depth habitats. We also did not identify any convincing candidate loci evidential for adaptation along a depth gradient and a transplant experiment showed no indications of local adaptation to living in the deep based on investigating growth and survival. Hence, the shallow‐water and the deep‐water morphotypes seem to be a result of phenotypic plasticity rather than local adaptation to depth. In conclusion, our ddRAD approach revealed insight into the establishment of genetically distinct quagga mussel populations in three perialpine lakes and suggests that phenotypic plasticity and life history traits (broadcast spawner with high fecundity and dispersing pelagic larvae) facilitate the fast spread and colonization of various depth habitats by the quagga mussel.

Research examining episodic future thinking (EFT; i.e., imagining oneself in future contexts) in community samples has demonstrated reduced discounting of delayed rewards when personalized event cues are included to prompt EFT related to reward latencies. While this EFT effect was recently demonstrated in individuals with substance use disorders, it is not yet known if it manifests similarly in individuals with and without a significant incarceration history—the latter being at elevated risk for negative outcomes including criminal recidivism. Individuals with cocaine use disorder (n = 35) identified personally-relevant future events and participated in a computerized delay discounting task, involving decisions between smaller immediate rewards or larger delayed rewards with and without EFT cues. Individuals with (n = 19) and without (n = 16) a significant history of incarceration were identified using the Addiction Severity Index-Lite. A significant reduction in discounting rates was observed when event cues were included to promote EFT (p = 0.02); however, there was no main effect of incarceration history on discounting behavior, or interaction between episodic future thinking condition and incarceration history. Results suggest personalized cues included to evoke EFT reduce discounting behavior in individuals with cocaine use disorder, regardless of incarceration history. EFT–based interventions may therefore have promise to reduce impulsive decision-making in individuals with cocaine use disorder with and without a significant history of incarceration, potentially supporting improved outcomes with respect to both substance use and future criminality.

The Quality I paradigm utilizes an error prevention strategy to avert rework in construction. The effectiveness of this paradigm is questionable as rework has become an innate feature of practice. If rework is to be mitigated in construction projects, a new paradigm is needed to challenge conventional thinking and offer a different perspective on managing errors. We introduce a new paradigm, Quality II, by drawing on a narrative review, emerging best practices deployed in construction, and contemporary developments in safety (e.g., Safety II and III). The implications of a Quality II paradigm for theory development and practice are also examined. The contributions of this paper are twofold as we: (1) provide construction organizations with a new approach for managing and learning how to handle (i.e., learning through) errors, and thus provide them with the ability to adapt and respond to varying conditions effectively; and (2) align Quality II with contemporary safety paradigms to offset competing demands enabling construction organizations to maximize the use of their limited resources better. By curbing rework, the performance and productivity of projects and the profitability of construction organizations will improve.

Objective To identify the outcomes considered important, and factors influencing the patient experience, for parents and caregivers of children presenting to hospital with a severe acute exacerbation of asthma. This work contributes to the outcome-identification process in developing a core outcome set (COS) for future clinical trials in children with severe acute asthma.Design A qualitative study involving semistructured interviews with parents and caregivers of children who presented to hospital with a severe acute exacerbation of asthma.Setting Hospitals in 12 countries associated with the global Pediatric Emergency Research Networks, including high-income and middle-income countries. Interviews were conducted face-to-face, by teleconference/video-call, or by phone.Findings Overall, there were 54 interviews with parents and caregivers; 2 interviews also involved the child. Hospital length of stay, intensive care unit or high-dependency unit (HDU) admission, and treatment costs were highlighted as important outcomes influencing the patient and family experience. Other potential clinical trial outcomes included work of breathing, speed of recovery and side effects. In addition, the patient and family experience was impacted by decision-making leading up to seeking hospital care, transit to hospital, waiting times and the use of intravenous treatment. Satisfaction of care was related to communication with clinicians and frequent reassessment.Conclusions This study provides insight into the outcomes that parents and caregivers believe to be the most important to be considered in the process of developing a COS for the treatment of acute severe exacerbations of asthma.

Abstract Background Most studies investigating the association between physical activity (PA) and the risk of type 2 diabetes are derived from self-reported questionnaires, with limited evidence using device-based measurements. Therefore, this study aimed to investigate the dose–response relationship between device-measured PA and incident type 2 diabetes. Methods This prospective cohort study included 40,431 participants of the UK Biobank. Wrist-worn accelerometers were used to estimate total, light, moderate, vigorous and moderate-to-vigorous PA. The associations between PA and incident type 2 diabetes were analysed using Cox-proportional hazard models. The mediating role of body mass index (BMI) was tested under a causal counterfactual framework. Results The median follow-up period was 6.3 years (IQR: 5.7–6.8), with 591 participants developing type 2 diabetes. Compared to those achieving 600 min/week were at 49% (95% CI 62–32%), 62% (95% CI 71–50%) and 71% (95% CI 80–59%) lower risk of type 2 diabetes, respectively. For vigorous PA, compared to those achieving 75 min/week were at 38% (95% CI 48–33%), 48% (95% CI 64–23%) and 64% (95% CI 78–42%) lower type 2 diabetes risk, respectively. Twelve per cent and 20% of the associations between vigorous and moderate PA and type 2 diabetes were mediated by lower BMI, respectively. Conclusions PA has clear dose-response relationship with a lower risk of type 2 diabetes. Our findings support the current aerobic PA recommendations but suggest that additional PA beyond the recommendations is associated with even greater risk reduction. Trial registration The UK Biobank study was approved by the North West Multi-Centre Research Ethics Committee (Ref 11/NW/0382 on June 17, 2011).

Aberrant androgen receptor (AR) signaling drives prostate cancer (PC), and it is a key therapeutic target. Although initially effective, the generation of alternatively spliced AR variants (AR-Vs) compromises efficacy of treatments. In contrast to full-length AR (AR-FL), AR-Vs constitutively activate androgenic signaling and are refractory to the current repertoire of AR-targeting therapies, which together drive disease progression. There is an unmet clinical need, therefore, to develop more durable PC therapies that can attenuate AR-V function. Exploiting the requirement of coregulatory proteins for AR-V function has the capacity to furnish tractable routes for attenuating persistent oncogenic AR signaling in advanced PC. DNA-PKcs regulates AR-FL transcriptional activity and is upregulated in both early and advanced PC. We hypothesized that DNA-PKcs is critical for AR-V function. Using a proximity biotinylation approach, we demonstrated that the DNA-PK holoenzyme is part of the AR-V7 interactome and is a key regulator of AR-V–mediated transcription and cell growth in models of advanced PC. Crucially, we provide evidence that DNA-PKcs controls global splicing and, via RBMX, regulates the maturation of AR-V and AR-FL transcripts. Ultimately, our data indicate that targeting DNA-PKcs attenuates AR-V signaling and provide evidence that DNA-PKcs blockade is an effective therapeutic option in advanced AR-V–positive patients with PC.

Background Computer-assisted interpretation of single-lead ECG is the preliminary method for clinicians to flag and further evaluate an arrhythmia of clinical importance for acutely ill patients. Critical scrutiny of novel detection algorithms is lacking, particularly in external real-world data sets. This study’s objective was to evaluate a hybrid machine learning model’s ability to classify eight arrhythmias from a single-lead ECG signal from acutely ill patients.Methods This cross-sectional external retrospective evaluation of a previously trained hybrid machine learning model against an ECG reading team in the setting of home hospital care (acute care delivered at home substituting for traditional hospital care) draws from patients admitted at two hospitals in Boston, Massachusetts, USA between 12 June 2017 and 23 November 2019. We calculated classifier statistics for each arrhythmia, all arrhythmias and strips where the model identified normal sinus rhythm.Results The model analysed 2 680 162 min of single-lead ECG data from 423 patients and identified 691 478 arrhythmias. Patients had a mean age of 70 years (SD, 18), 60% were female and 45% were white. For any arrhythmia, the model had a sensitivity of 98%, a specificity of 100%, an accuracy of 98%, a positive predictive value of 100%, a negative predictive value of 93% and an F1 Score of 99%. Performance was best for pause (F1 Score, 99%) and worst for paroxysmal supraventricular tachycardia (F1 Score, 92%). The model’s false positive rate for any arrhythmia was 0.2%, ranging from 0.4% for pause to 7.2% for paroxysmal supraventricular tachycardia. The false negative rate for any arrhythmia was 1.9%.Conclusions A hybrid machine learning model was effective at classifying common cardiac arrhythmias from a single-lead ECG in real-world data.

Background: Since tobacco smoking represents the most established risk factor for bladder cancer, we sought to assess the ecological association between tobacco smoking prevalence and bladder cancer incidence and to contrast it with lung cancer. Methods: The annual overall tobacco smoking prevalence rates were extracted from the Report of the Surgeon General and the Center for Disease Control between 1953 and 1983. The overall age-adjusted incidence rates for bladder and lung cancers were derived from the Surveillance, Epidemiology, and End Results database between 1983 and 2013 (30-year latency period). Weighted least square regression models were used to assess bladder and lung cancer incidence rate differences (IRD) related to trends in tobacco smoking prevalence. A Wald test was used to compare whether the prevalence of tobacco smoking, as an explanatory variable, differentially predicts bladder versus lung cancer incidence rates. Results: The associations between tobacco smoking prevalence and bladder cancer incidence were not significant in the overall (IRD = +0.04; 95%CI (−0.14; +0.22); p = 0.63), male (IRD = +0.07; 95%CI (−0.09; +0.23); p = 0.37), or female (IRD = +0.12; 95%CI (−0.01; +0.25); p = 0.06) populations. There was an association between tobacco smoking prevalence and lung cancer incidence in the overall (IRD: +3.55; 95%CI ( +3.09; +4.00); p < 0.001), male (IRD: +4.82; 95%CI (+4.44; +5.20); p < 0.001), and female (IRD: +3.55; 95%CI (+3.12; +3.99); p < 0.001) populations. The difference between the observed associations of tobacco smoking prevalence with bladder versus lung cancer incidence was also significant in all examined populations (p < 0.001). Conclusions: Variations in tobacco smoking prevalence only partially explained the trends in the incidence of bladder cancer, indicating that its etiology is complex.

Abstract Non-contrast head CT (NCCT) is extremely insensitive for early ( 0.98). When this 150 CT test set was expanded to include a total of 364 CT scans with a more heterogeneous distribution of infarct locations (94 stroke-negative, 270 stroke-positive mixed territory infarcts), model sensitivity was 97%, specificity 99%, for detection of infarcts larger than the 70 mL volume threshold used for patient selection in several major randomized controlled trials of thrombectomy treatment.

In plants, macroautophagy/autophagy is an essential mechanism responsible for a large variety of processes throughout the plant’s lifecycle, including nutrient processing, immunity, stress responses and senescence. Previous studies had observed the presence of autophagosomes in an Arabidopsis sexual reproduction system that prevents self-fertilization (self-incompatibility), but their requirement in this pathway was unclear. Using autophagy-deficient mutants, we have recently found that autophagy is a key contributor in the Arabidopsis self-incompatibility response to reject self-pollen.

Abstract Background Regular participation in resistance exercise is known to have broad-ranging health benefits and for this reason is prominent in the current physical activity guidelines. Recovery after such exercise is important for several populations across the age range and nutritional strategies to enhance recovery and modulate post-exercise physiological processes are widely studied, yet effective strategies remain elusive. Vitamin K2 supplementation has emerged as a potential candidate, and the aim of the current study, therefore, is to test the hypothesis that vitamin K2 supplementation can accelerate recovery, via modulation of the underlying physiological processes, following a bout of resistance exercise in young and older adults. Methods The current study is a two-arm randomised controlled trial which will be conducted in 80 (40 young (≤40 years) and 40 older (≥65 years)) adults to compare post-exercise recovery in those supplemented with vitamin K2 or placebo for a 12-week period. The primary outcome is muscle strength with secondary outcomes including pain-free range of motion, functional abilities, surface electromyography (sEMG) and markers of inflammation and oxidative stress. Discussion Ethical approval has been granted by the College of Medical Veterinary and Life Sciences Ethical Committee at the University of Glasgow (Project No 200190189) and recruitment is ongoing. Study findings will be disseminated through a presentation at scientific conferences and in scientific journals. Trial registration ClinicialTrials.gov NCT04676958. Prospectively registered on 21 December 2020.

There has been a wealth of research that has examined the nature of rework in construction. Progress toward addressing the rework problem has been limited—it still plagues practice, adversely impacting a project’s performance. Almost all rework studies have focused on determining its proximal or root causes and therefore have overlooked the conditions that result from its manifestation. In filling this void, this paper draws upon our previous empirical studies, amongst others, to provide a much-needed theoretical framing to understand better why rework occurs, what its consequences are, and how it can be mitigated during construction. The theoretical framing we derive from our review provides construction organizations and their projects with a realization that the journey to mitigating rework begins with creating an error-mastery culture comprising authentic leadership, psychological safety, an error-management orientation, and resilience. We suggest that, once an error-mastery culture is established within construction organizations and their projects, they will be better positioned to realize the benefits of the techniques, tools, and technologies espoused to address rework, such as the Last Planner® and building information modeling. We also provide directions for future research and identify implications for practice so that strides toward rework mitigation in construction can be made.

Abstract Background Studies on physical activity (PA) and mental health are largely limited to self-reported PA. This study aims to use prospective cohort data to investigate the association between device-measured PA and affective disorders. Methods A total of 37,327 participants from UK Biobank who had not had any prior affective disorder diagnoses were included in this prospective cohort study. Wrist-worn accelerometers were used to measure total, light (LPA), moderate (MPA), and vigorous (VPA) PA. Associations between PA domains and affective disorders were analysed using penalised splines in Cox proportional hazard models. Analyses were adjusted for other intensity-specific PA and sociodemographic and lifestyle factors. Sensitivity analyses were conducted adjusting for body mass index and longstanding illnesses as well as excluding events in the first 2 years of follow-up. Preventable fractions for the population were estimated for MPA and VPA. Results Over a median follow-up of 6.8 years, 1262 (3.4%) individuals were diagnosed with affective disorders. Replacing 30 min of sedentary behaviour in a week with MPA (HR 0.95, 95% CI 0.94–0.97) or VPA (HR 0.91, 95% CI 0.85–0.98) was associated with lower risk of affective behaviours, up to 500 and 120 min of MPA and VPA. Assuming causality, 5.14% and 18.88% of affective disorders could have been prevented if MPA ≥150 min/week and VPA ≥75 min/week were achieved, respectively, across the study population. Conclusions Device-measured MPA and VPA were associated with lower risk of affective disorders. The potential mental health benefits of MPA continue to accrue above the current World Health Organization recommendation.

Abstract Background Depression and anxiety are the leading mental health problems worldwide; depression is ranked as the leading cause of global disability with anxiety disorders ranked sixth. Preventive strategies based on the identification of modifiable factors merit exploration. The aim of the present study was to investigate the associations of handgrip strength (HGS) with incident depression and anxiety and to explore how these associations differ by socio‐demographic, lifestyle, and health‐related factors. Methods The analytic sample comprised 162 167 participants (55% women), aged 38–70 years, from the UK Biobank prospective cohort study. HGS was assessed at baseline using dynamometry. Depression and anxiety were extracted from primary care and hospital admission records. Cox proportional models were applied, with a 2 year landmark analysis, to investigate the associations between HGS and incident depression and anxiety. Results Of the 162 167 participants included, 5462 (3.4%) developed depression and 6614 (4.1%) anxiety, over a median follow‐up period of 10.0 years (inter‐quartile range: 9.3–10.8) for depression and 9.9 (inter‐quartile range: 9.0–10.8) for anxiety. In the fully adjusted model, a 5 kg lower HGS was associated with a 7% (HR: 1.07 [95% CI: 1.05, 1.10]; P

Abstract Background Coronavirus disease-19 (COVID-19) infection causes persistent health problems such as breathlessness, chest pain and fatigue, and therapies for the prevention and early treatment of post-COVID-19 syndromes are needed. Accordingly, we are investigating the effect of a resistance exercise intervention on exercise capacity and health status following COVID-19 infection. Methods A two-arm randomised, controlled clinical trial including 220 adults with a diagnosis of COVID-19 in the preceding 6 months. Participants will be classified according to clinical presentation: Group A, not hospitalised due to COVID but persisting symptoms for at least 4 weeks leading to medical review; Group B, discharged after an admission for COVID and with persistent symptoms for at least 4 weeks; or Group C, convalescing in hospital after an admission for COVID. Participants will be randomised to usual care or usual care plus a personalised and pragmatic resistance exercise intervention for 12 weeks. The primary outcome is the incremental shuttle walks test (ISWT) 3 months after randomisation with secondary outcomes including spirometry, grip strength, short performance physical battery (SPPB), frailty status, contacts with healthcare professionals, hospitalisation and questionnaires assessing health-related quality of life, physical activity, fatigue and dyspnoea. Discussion Ethical approval has been granted by the National Health Service (NHS) West of Scotland Research Ethics Committee (REC) (reference: GN20CA537) and recruitment is ongoing. Trial findings will be disseminated through patient and public forums, scientific conferences and journals. Trial registration ClinicialTrials.gov NCT04900961 . Prospectively registered on 25 May 2021

Abstract Background Understanding how and why de-implementation of low-value practices is sustained remains unclear. The Paediatric Research in Emergency Departments International CollaboraTive (PREDICT) Bronchiolitis Knowledge Translation (KT) Study was a cluster randomised controlled trial conducted in 26 Australian and New Zealand hospitals (May-November 2017). Results showed targeted, theory-informed interventions (clinical leads, stakeholder meetings, train-the-trainer workshop, targeted educational package, audit/feedback) were effective at reducing use of five low-value practices for bronchiolitis (salbutamol, glucocorticoids, antibiotics, adrenaline and chest x-ray) by 14.1% in acute care settings. The primary aim of this study is to determine the sustainability (continued receipt of benefits) of these outcomes at intervention hospitals two-years after the removal of study supports. Secondary aims are to determine sustainability at one-year after removal of study support at intervention hospitals; improvements one-and-two years at control hospitals; and explore factors that influence sustainability at intervention hospitals and contribute to improvements at control hospitals. Methods A mixed-methods study design. The quantitative component is a retrospective medical record audit of bronchiolitis management within 24 hours of emergency department (ED) presentations at 26 Australian (n = 20) and New Zealand (n = 6) hospitals, which participated in the PREDICT Bronchiolitis KT Study. Data for a total of 1800 infants from intervention and control sites (up to 150 per site) will be collected to determine if improvements (i.e., no use of all five low-value practices) were sustained two- years (2019) post-trial (primary outcome; composite score); and a further 1800 infants from intervention and control sites will be collected to determine sustained improvements one- year (2018) post-trial (secondary outcome). An a priori definition of sustainability will be used. The qualitative component will consist of semi-structured interviews with three to five key emergency department and paediatric inpatient medical and nursing staff per site (total n = 78-130). Factors that may have contributed to sustaining outcomes and/or interventions will be explored and mapped to an established sustainability framework. Discussion This study will improve our understanding of the sustainability of evidence-based bronchiolitis management in infants. Results will also advance implementation science research by informing future de-implementation strategies to reduce low-value practices and sustain practice change in paediatric acute care. Trial registration Australian and New Zealand Clinical Trials Registry No: ACTRN12621001287820.

Abstract Background This study aimed to investigate the associations of grip strength with incidence and mortality from dementia and whether these associations differ by sociodemographic and lifestyle factors. Methods A total of 466 788 participants of the UK Biobank (median age 56.5 years, 54.5% women). The outcome was all‐cause dementia incidence and mortality and the exposure was grip strength. Grip strength was assessed using a Jamar J00105 hydraulic hand dynamometer. Results Excluding the first 2 years of follow‐up (landmark analysis), mean follow‐up was 9.1 years (inter‐quartile range: 8.3; 9.7) for incidence and 9.3 (inter‐quartile range: 8.7; 10.0) for mortality. During this time, 4087 participants developed dementia, and 1309 died from it. Lower grip strength was associated with a higher risk of dementia incidence and mortality independent of major confounding factors (P

AimTo explore the factors influencing the use of high-flow nasal cannula (HFNC) therapy for infants with bronchiolitis.DesignQualitative approach using semi-structured interviews.MethodsThe semi-structured interviews (face-to-face or virtual) were conducted between September 2020 and February 2021. Deductive content analysis was used to map key influencing factors for use of HFNC therapy to the Theoretical Domains Framework (TDF).ResultsNineteen interviews were undertaken before reaching thematic saturation (7 nurses, 12 doctors) in emergency departments and paediatric wards from four purposively selected hospitals in Australia and New Zealand. Influencing factors were mapped to eight domains in the TDF with 21 themes identified. Main findings included: (1) Health professionals' expectations of HFNC therapy on patient deterioration, work of breathing and oxygenation; (2) Staff emotions relating to concern and anxiety about deterioration and “need to do something”; (3) Social influences from other health professionals and parents and (4) Environmental factors relating to logistics of care and patient transfer considerations. These factors, combined with the ready availability of HFNC equipment and health professionals having the required skills to administer the therapy, contributed to its initiation.ConclusionIndividual/personal and contextual/environmental factors contribute to the use of HFNC therapy for infants with bronchiolitis. It is evident these influences contribute substantially to increased use, despite evidence-based guidelines recommending a more nuanced approach to this therapy. These findings will inform a targeted implementation intervention to promote evidence-based use of HFNC therapy in infants with bronchiolitis.

Abstract Background Literature on factors influencing medication adherence within paediatric clinical trials is sparse. The Paracetamol and Ibuprofen in the Primary Prevention of Asthma in Tamariki (PIPPA Tamariki) trial is an open-label, randomised controlled trial aiming to determine whether paracetamol treatment, compared with ibuprofen treatment, as required for fever and pain in the first year of life, increases the risk of asthma at age six years. To inform strategies for reducing trial medication crossovers, understanding factors influencing the observed ibuprofen-to-paracetamol crossovers (non-protocol adherence) is vital. The aim of this study was to investigate the factors influencing the decision-making process when administering or prescribing ibuprofen to infants that may contribute to the crossover events in the PIPPA Tamariki trial. Methods Constructivist grounded theory methods were employed. We conducted semi-structured interviews of caregivers of enrolled PIPPA Tamariki infants and healthcare professionals in various healthcare settings. Increasing theoretical sensitivity of the interviewers led to theoretical sampling of participants who could expand on the teams’ early constructed codes. Transcribed interviews were coded and analysed using the constant comparative method of concurrent data collection and analysis. Results Between September and December 2020, 20 participants (12 caregivers; 8 healthcare professionals) were interviewed. We constructed a grounded theory of prioritising infant welfare that represents a basic social process when caregivers and healthcare professionals medicate feverish infants. This process comprises three categories: historical, trusting relationships and being discerning; and is modified by one condition: being conflicted. Participants bring with them historical ideas. Trusting relationships with researchers, treating clinicians and family play a central role in enabling participants to challenge historical ideas and be discerning. Trial medication crossovers occur when participants become conflicted, and they revert to historical practices that feel familiar and safer. Conclusions We identified factors and a basic social process influencing ibuprofen use in infants and trial medication crossover events, which can inform strategies for promoting adherence in the PIPPA Tamariki trial. Future studies should explore the role of trusting relationships between researchers and treating clinicians when conducting research.

Abstract Background Bayesian methods are increasing in popularity in clinical research. The design of Bayesian clinical trials requires a prior distribution, which can be elicited from experts. In diseases with international differences in management, the elicitation exercise should recruit internationally, making a face-to-face elicitation session expensive and more logistically challenging. Thus, we used a remote, real-time elicitation exercise to construct prior distributions. These elicited distributions were then used to determine the sample size of the Bronchiolitis in Infants with Placebo Versus Epinephrine and Dexamethasone (BIPED) study, an international randomised controlled trial in the Pediatric Emergency Research Network (PERN). The BIPED study aims to determine whether the combination of epinephrine and dexamethasone, compared to placebo, is effective in reducing hospital admission for infants presenting with bronchiolitis to the emergency department. Methods We developed a Web-based tool to support the elicitation of the probability of hospitalisation for infants with bronchiolitis. Experts participated in online workshops to specify their individual prior distributions, which were aggregated using the equal-weighted linear pooling method. Experts were then invited to provide their comments on the aggregated distribution. The average length criterion determined the BIPED sample size. Results Fifteen paediatric emergency medicine clinicians from Canada, the USA, Australia and New Zealand participated in three workshops to provide their elicited prior distributions. The mean elicited probability of admission for infants with bronchiolitis was slightly lower for those receiving epinephrine and dexamethasone compared to supportive care in the aggregate distribution. There were substantial differences in the individual beliefs but limited differences between North America and Australasia. From this aggregate distribution, a sample size of 410 patients per arm results in an average 95% credible interval length of less than 9% and a relative predictive power of 90%. Conclusion Remote, real-time expert elicitation is a feasible, useful and practical tool to determine a prior distribution for international randomised controlled trials. Bayesian methods can then determine the trial sample size using these elicited prior distributions. The ease and low cost of remote expert elicitation mean that this approach is suitable for future international randomised controlled trials. Trial registration ClinicalTrials.gov NCT03567473

Abstract Background Ethnic differences in cardiovascular disease (CVD) risk have been known for decades, but a systematic exploration of how exposure and susceptibility to risk factors may contribute is lacking. This study aimed to investigate the potential impact of differential exposure and susceptibility between South Asian, Black, and White individuals. Methods This is a population-based prospective cohort study of UK Biobank participants with a median follow-up of 11.3 years. The association between ethnic group and CVD risk was studied. Additional risk factors were then adjusted to examine mediations. Moderation analysis was conducted to identify whether risk factors had a stronger association in the ethnic minority groups. Population attributable fractions were also calculated to quantify the relative contributions of risk factors for each ethnic group. Results When adjusted for only age and sex, there was a higher risk of CVD among South Asian (n=8815; HR [95% CI] 1.69 [1.59–1.79]) and Black (n=7526; HR [95% CI] 1.12 [1.03–1.22]) compared with White participants (n=434,809). The excess risk of Black participants was completely attenuated following adjustment for deprivation. Compared with White participants, the associations of BMI, triglycerides, and HbA1c with CVD were stronger in South Asians. Adiposity was attributable to the highest proportion of CVD regardless of ethnicity. Smoking had the second largest contribution to CVD among White and Black participants, and HbA1c among South Asian participants. Conclusions Adiposity is an important risk factor for CVD regardless of ethnicity. Ethnic inequalities in CVD incidence may be best tackled by targeting interventions according to ethnic differences in risk profiles.

Abstract Stroke is a leading cause of death and disability. The ability to quickly identify the presence of acute infarct and quantify the volume on magnetic resonance imaging (MRI) has important treatment implications. We developed a machine learning model that used the apparent diffusion coefficient and diffusion weighted imaging series. It was trained on 6,657 MRI studies from Massachusetts General Hospital (MGH; Boston, USA). All studies were labelled positive or negative for infarct (classification annotation) with 377 having the region of interest outlined (segmentation annotation). The different annotation types facilitated training on more studies while not requiring the extensive time to manually segment every study. We initially validated the model on studies sequestered from the training set. We then tested the model on studies from three clinical scenarios: consecutive stroke team activations for 6-months at MGH, consecutive stroke team activations for 6-months at a hospital that did not provide training data (Brigham and Women’s Hospital [BWH]; Boston, USA), and an international site (Diagnósticos da América SA [DASA]; Brazil). The model results were compared to radiologist ground truth interpretations. The model performed better when trained on classification and segmentation annotations (area under the receiver operating curve [AUROC] 0.995 [95% CI 0.992–0.998] and median Dice coefficient for segmentation overlap of 0.797 [IQR 0.642–0.861]) compared to segmentation annotations alone (AUROC 0.982 [95% CI 0.972–0.990] and Dice coefficient 0.776 [IQR 0.584–0.857]). The model accurately identified infarcts for MGH stroke team activations (AUROC 0.964 [95% CI 0.943–0.982], 381 studies), BWH stroke team activations (AUROC 0.981 [95% CI 0.966–0.993], 247 studies), and at DASA (AUROC 0.998 [95% CI 0.993–1.000], 171 studies). The model accurately segmented infarcts with Pearson correlation comparing model output and ground truth volumes between 0.968 and 0.986 for the three scenarios. Acute infarct can be accurately detected and segmented on MRI in real-world clinical scenarios using a machine learning model.

Abstract Background Sarcopenia is defined as the loss of muscle mass and strength. Despite the seriousness of this disease, a single diagnostic criterion has not yet been established. Few studies have reported the prevalence of sarcopenia globally, and there is a high level of heterogeneity between studies, stemmed from the diagnostic criteria of sarcopenia and the target population. The aims of this systematic review and meta‐analysis were (i) to identify and summarize the diagnostic criteria used to define sarcopenia and severe sarcopenia and (ii) to estimate the global and region‐specific prevalence of sarcopenia and severe sarcopenia by sociodemographic factors. Methods Embase, MEDLINE, and Web of Science Core Collections were searched using relevant MeSH terms. The inclusion criteria were cross‐sectional or cohort studies in individuals aged ≥18 years, published in English, and with muscle mass measured using dual‐energy x‐ray absorptiometry, bioelectrical impedance, or computed tomography (CT) scan. For the meta‐analysis, studies were stratified by diagnostic criteria (classifications), cut‐off points, and instruments to assess muscle mass. If at least three studies reported the same classification, cut‐off points, and instrument to measure muscle mass, they were considered suitable for meta‐analysis. Following this approach, 6 classifications and 23 subgroups were created. Overall pooled estimates with inverse‐variance weights obtained from a random‐effects model were estimated using the metaprop command in Stata. Results Out of 19 320 studies, 263 were eligible for the narrative synthesis and 151 for meta‐analysis (total n = 692 056, mean age: 68.5 years). Using different classifications and cut‐off points, the prevalence of sarcopenia varied between 10% and 27% in the studies included for meta‐analysis. The highest and lowest prevalence were observed in Oceania and Europe using the European Working Group on Sarcopenia in Older People (EWGSOP) and EWGSOP2, respectively. The prevalence ranged from 8% to 36% in individuals

Abstract The aims of the current study, therefore, were to compare (1) free-living MPS and (2) muscle and metabolic adaptations to resistance exercise in South Asian and white European adults. Eighteen South Asian and 16 White European men were enrolled in the study. Free-living muscle protein synthesis was measured at baseline. Muscle strength, body composition, resting metabolic rate, VO2max and metabolic responses (insulin sensitivity) to a mixed meal were measured at baseline and following 12 weeks of resistance exercise training. Free-living muscle protein synthesis was not different between South Asians (1.48 ± 0.09%/day) and White Europeans (1.59 ± 0.15%/day) (p = 0.522). In response to resistance exercise training there were no differences, between South Asians and White Europeans, muscle mass, lower body strength or insulin sensitivity. However, there were differences between the ethnicities in response to resistance exercise training in body fat, resting carbohydrate and fat metabolism, blood pressure, VO2max and upper body strength with responses less favourable in South Asians. In this exploratory study there were no differences in muscle protein synthesis or anabolic and metabolic responses to resistance exercise, yet there were less favourable responses in several outcomes. These findings require further investigation.

Machine learning (ML) algorithms to detect critical findings on head CTs may expedite patient management. Most ML algorithms for diagnostic imaging analysis utilize dichotomous classifications to determine whether a specific abnormality is present. However, imaging findings may be indeterminate, and algorithmic inferences may have substantial uncertainty. We incorporated awareness of uncertainty into an ML algorithm that detects intracranial hemorrhage or other urgent intracranial abnormalities and evaluated prospectively identified, 1000 consecutive noncontrast head CTs assigned to Emergency Department Neuroradiology for interpretation. The algorithm classified the scans into high (IC+) and low (IC-) probabilities for intracranial hemorrhage or other urgent abnormalities. All other cases were designated as No Prediction (NP) by the algorithm. The positive predictive value for IC+ cases (N = 103) was 0.91 (CI: 0.84-0.96), and the negative predictive value for IC- cases (N = 729) was 0.94 (0.91-0.96). Admission, neurosurgical intervention, and 30-day mortality rates for IC+ was 75% (63-84), 35% (24-47), and 10% (4-20), compared to 43% (40-47), 4% (3-6), and 3% (2-5) for IC-. There were 168 NP cases, of which 32% had intracranial hemorrhage or other urgent abnormalities, 31% had artifacts and postoperative changes, and 29% had no abnormalities. An ML algorithm incorporating uncertainty classified most head CTs into clinically relevant groups with high predictive values and may help accelerate the management of patients with intracranial hemorrhage or other urgent intracranial abnormalities.

Abstract Background Previous cohort studies have investigated the relationship between self-reported physical activity (PA) and dementia. Evidence from objective device-measured PA data is lacking. This study aimed to explore the association of device-measured PA with the risk of dementia incidence and common subtypes (Alzheimer’s disease [AD] and vascular dementia) using the UK Biobank study. Methods 84,854 participants (55.8% women), invited to participate in the device-measured PA between 2013 and 2015, were included in this prospective cohort study. Wrist accelerometers were used to measure light, moderate, vigorous, moderate-to-vigorous PA (MVPA) and total PA intensity and duration (MET/min/week). Incident dementia (fatal and non-fatal) was extracted from hospital episodes records for incidence and death register for mortality. Incidence follow-up was carried out until the end of March 2021in England and Scotland and the end of March 2018 in Wales. Mortality data were available until February 2021. Nonlinear associations were first investigated using penalised cubic splines fitted in the Cox proportional hazard models. In addition, using MVPA, five categories were created. Associations of these categories with the outcomes were investigated using Cox proportional hazard models. Analyses were adjusted for sociodemographic, lifestyle and health-related factors. Results After a median follow-up of 6.3 years, 678 individuals were diagnosed with dementia. Evidence of nonlinearity was observed for all PA modes and all-cause dementia. For categories of MVPA, there was a significant trend towards a low risk of overall dementia when higher levels of MVPA were achieved (HRtrend 0.66 [95% CI 0.62 to 0.70]. The lowest risk was identified in individuals who performed more than 1200 MET/min/week, those who had 84% (95% CI 0.12 to 0.21) lower risk of incident dementia compared to those who performed

The electric vehicle market is an increasingly important aspect of the automotive industry. However, as a relatively new technology, several issues remain present within the industry. An analysis is utilised to examine these issues, along with how they affect the industry and how they can be tackled. Several key issues that affect the electric vehicle market, as well as how efforts to address these issues influence the market, are identified. The analysis also includes the examination of ethical issues, with the issues that arise from the production of raw materials for electric vehicles. The analysis and examination of ethical issues display a wide range of problems in the industry. However, it did highlight the efforts being made to lessen the effect of these problems by various groups, such as regulation by EU and US governing bodies on the materials mined. From this analysis, this paper identifies that many of the other factors examined are directly or indirectly influenced by political and economic factors, also examined in this review. This highlights the impact that governing bodies and businesses have on a vast number of issues that are present within the market and how they can resolve the harmful factors examined.